TGF? and adenosine are ubiquitous molecules in the tumor microenvironment that participate in the regulation of various stages of tumor progression and metastasis. Our recent studies have demonstrated an essential role for TGF? signaling in the differentiation of CD39+CD73+ terminally-differentiated mononuclear myeloid cells (TDMMC) during tumor progression. We discovered that TDMCCs in tumor tissue generate high levels of adenosine via unique co-expression of CD39 and CD73 regulated by TGF?. Adenosine is a key regulator of inflammation, angiogenesis and immune cell function. Our novel data show that adenosine generated by TDMMC in a paracrine manner decreases fibroblast responses to TGF?. Loss of TGF? signaling on fibroblasts in tumor tissue correlates with increase metastasis and poor survival of cancer patients. We hypothesize that that CD39+CD73+ myeloid cells negatively regulate TGF? effects on tumor-associated fibroblasts promoting them, via activation of A2 adenosine receptors, to cells with pro-metastatic and pro-tumorigenic properties. We propose to test this hypothesis in Specific Aim 1 by examining the functional significance of CD39 and CD73 expression on TDMMC in regulation fibroblasts functions in vitro. In Specific Aim 2, we will determine the molecular mechanisms of interactions between adenosine signaling and TGF? signaling on cancer-associated fibroblasts. Finally, in Specific Aim 3, we will determine the role of adenosine receptors on fibroblasts in tumor progression, microenvironmental changes and metastasis. We anticipate that findings from the proposed studies will provide new insight into the depth and complexity of mechanisms that mediate the effects of adenosine on TGF? signaling during tumor progression. Our findings will aid in developing novel therapeutic strategies to decrease tumor progression and metastases.